Everyone looking at Abl these days is trying to wiggle their way around T315 and Ariad’s latest go is described in the app: WO/2007/021937 with a series of styrene-purines. They look to be a follow-on series to the earlier purine stuff described elsewhere.

Structures for their two previous SRC/ABL leads: AP23464 and AP23451 were disclosed but afaik AP24534 has not.

But refs 16-18 are the apps which cover this series and that’s about it for the 3 pyrroles. The 2-pyrrole substructure can be seen all over the place from things like the DNA/Roche aurora indoles, to chk1, to plenty of others. A subtle difference, but all the difference given how these hit the ERK hinge.

Anyhow, in going after the ERK gatekeeper with the pyrrole, it is surprising to find JNK3 activity since the JNK gatekeeper is methionine rather then glutamine. Interestingly the ligand adopts a flipped conformation in JNK3 more reminiscent of what you’d expect from the pyrrol-2-yl-pyrazole, like indoles, benzimidazoles and such.

The way the paper is worded it seems as though the selectivity was worked out in advance of the structures being obtained. Heh. If nothing else, the PDB’s give a good example of a pyrrole tightly hydrogen bound to GLN. 2OJG, 2OJI, 2OJJ, 2OK1,